Drug resistance of bladder cancer cells through activation of ABCG2 by FOXM1

Abstract

Recurrence is a serious problem in patients with bladder cancer. The hypothesis for recurrence was that the proliferation of drug-resistant cells was reported, and this study focused on drug resistance due to drug efflux. Previous studies have identified FOXM1 as the key gene for recurrence. We found that FOXM1 inhibition decreased drug efflux activity and increased sensitivity to Doxorubicin. Therefore, we examined whether the expression of ABC transporter gene related to drug efflux is regulated by FOXM1. As a result, ABCG2, one of the genes involved in drug efflux, has been identified as a new target for FOXM1. We also demonstrated direct transcriptional regulation of ABCG2 by FOXM1 using ChIP assay. Consequently, in the presence of the drug, FOXM1 is proposed to directly activate ABCG2 to increase the drug efflux activation and drug resistance, thereby involving chemoresistance of bladder cancer cells. Therefore, we suggest that FOXM1 and ABCG2 may be useful targets and important parameters in the treatment of bladder cancer.

JNK signaling in cancer cell survival

“…For example, JNK contributes to the resistance of stem‐like glioblastoma cells to temozolomide. Moreover, O 6 ‐methylguanine DNA methyltransferase (MGMT) seems to be an important mediator in this context, since JNK activation induces MGMT expression; when JNK activity is inhibited, MGMT expression and temozolomide resistance decrease . Cisplatin is a chemotherapeutic drug used widely for the treatment of human cancers.…”

“…JNK inhibition reduced the PTMA protein stability and sensitized HCC cells to cisplatin. ATP‐binding cassette subfamily G member 2 (ABCG2), a half‐transporter belonging to the G subfamily of ATP‐binding cassette transporter (ABC) transporter genes, plays an important role in multidrug resistance . Zhu et al, showed that JNK1 signaling is involved in multidrug resistance of colon cancer cells.…”

“…Moreover, O 6 -methylguanine DNA methyltransferase (MGMT) seems to be an important mediator in this context, since JNK activation induces MGMT expression; when JNK activity is inhibited, MGMT expression and temozolomide resistance decrease. 84 Cisplatin is a chemotherapeutic drug used widely for the treatment of human cancers. Accumulating data show that the resistance of non-small cell lung cancer (NSCLC) cells and HCC to cisplatin is also induced via regulation of JNK signaling.…”

“…ATP-binding cassette subfamily G member 2 (ABCG2), a half-transporter belonging to the G subfamily of ATP-binding cassette transporter (ABC) transporter genes, plays an important role in multidrug resistance. 84 Zhu et al, 86 showed that JNK1 signaling is involved in multidrug resistance of colon cancer cells. Blocking the JNK pathway markedly decreased the mRNA and protein expression and transport activity of ABCG2 in a hydroxycamptothecin-resistant human colon cancer cell line.…”

CCN2 promotes drug resistance in osteosarcoma by enhancing ABCG2 expression

“…Many chemotherapeutics are known to be ABCG2 substrates, such as mitoxantrone, methotrexate, doxorubicin, diflomotecan, topotecan, and SN-38 (an active metabolite of irinotecan; Erdei et al, 2018;Hira & Terada, 2018). ABCG2 activity is linked to chemoresistance in various cancers, including ovarian cancer , pancreatic cancer (Stern et al, 2018), lung (Xie et al, 2018) and bladder cancer (Roh et al, 2018). CCN family member 2 (CCN2) (also known as connective tissue growth factor [CTGF]) acts as a multifunctional signaling modulator in various biologic or pathologic processes (Luft, 2008).…”